A reduction in central serotenergic (5-HT) neurotransmission is thought to play an important role in the etiology of major depression disorders (MDD). Treatments strategies that enhance 5-HT function are used to treat MDD symptoms. Evidence from basic and clinical studies indicates that dopamine (DA) input to the dorsal raphe nucleus (DRN), which contains the largest group of 5-HT neurons, plays a key role in the regulation of normal 5-HT neurotransmission. Furthermore, a degeneration of DA neurons in Parkinson's disease patients is frequently associated with a deficit in central 5-HT neurotransmission and the onset of MDD symptoms. Finally, results from clinical studies show that D,-like DA receptor agonists and DA releasing agents enhance the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs). Thus, understanding how DA regulates the 5-HT system at the level of the DRN may contribute significantly to the development of better treatment for MDD. Over the past two years we have studied the effect of DA on the excitability of DRN 5-HT neurons using the intracellular recording technique in brain slices. We have identified a novel D2-like DA receptors induced excitation in DRN 5-HT neurons. This electrophysiological response may represent a cellular substrate by which DA enhances central 5-HT neurotransmission. In this application, using electrophysiological, pharmacological and immunohistochemical techniques, we seek to characterize the detailed cellular mechanism by which D,-like DA receptor activation increases the excitability of DRN 5-HT neurons. The specific Aims are 1) To test the hypothesis that D2-like DA receptors induced membrane depolarization in DRN 5-HT neurons is mediated by a calcium-dependent cation non-selective current (IDA). 2) To test the hypothesis that calcium release from internal stores contributes to the activation of i'DA* 3) To identify the D2-like DA receptor subtypes(s) involved in the activation of 'DA* 4) To elucidate the signaling mechanism that mediates the activation of 'DA by D2-like DA receptor stimulation. We believe results from this proposal will better our understanding in the functional interaction between DA and 5-HT systems in the DRN, and may ultimately contribute to the search of novel and effective treatments strategies for major depression.